Synergistic enhancement of catalytic activity of InCl 3 - Me 3 SiCl combination towards carbon Ferrier rearrangement in glycal derivatives

InCl 3 (2 mol%) in combination with Me 3 SiCl (20 mol%) efficiently catalyze Ferrier rearrangement in a variety of glycal derivatives with different silyl nucleophiles to afford the corresponding C-pseudoglycals or unsaturated pyrans in nearly quantitative yields. The stereoselectivities of the C-glycosides are good to excellent in favor of the α -anomers. A stoichiometric amount of InCl 3 is necessary for similar transformations in the absence of Me 3 SiCl. The InCl 3 can be recovered and reused without any loss of its activity.


Introduction
Because of numerous applications, the synthesis of C-glycosides has attracted considerable attention during the last two decades.These are potential chiral building blocks for the synthesis of a number of biologically important macromolecules like palytoxin, spongistatin, halichondrin etc. 1 The pharmacological importance of naturally occurring C-nucleosides and inhibitory role of C-glycosides towards carbohydrate processing enzymes add more impetus in this direction. 2ecause of the presence of the double bond or cyano group, which can be readily functionalized, allyl C-pseudoglycals, 3 glycosyl cyanides or pyrans are attractive chiral synthetic intermediates. 4ince its first report 5 the Ferrier rearrangement has been extensively exploited for the Cglycosylation reactions of glycals.A variety of Lewis acids 6 and other reagents 7 have been utilized towards this end.However, many of the reported procedures have their own limitations in terms of yields, stereoselectivity, amount and reusability of the catalyst, besides the stringent experimental conditions in some cases.In an earlier report 6f we demonstrated that a stoichiometric amount of InCl 3 promotes carbon Ferrier rearrangement in glycal derivatives in excellent yields and stereoselectivities.While we were exploring the possibility of a catalytic version of InCl 3 mediated C-glycosylation, Baba et.al. 8 reported that a number of organic transformations can be efficiently carried out based on the combination catalyst incorporating InCl 3 and R 1 R 2 R 3 SiCl due to remarkable enhancement of Lewis acidity of such systems.We were delighted to observe that a combination of InCl 3 and Me 3 SiCl generates a highly efficient catalyst system in C-glycosylation of glycals.We present, herein, our results on Ferrier rearrangement in glycal derivatives using this combination catalyst (Schemes 1 and 2, Tables 1  and 2).

Results and Discussion
By varying the proportions of the InCl 3 -Me 3 SiCl combination (Table 1), the minimum catalyst load was established in the reaction of per-O-acetyl-D-glucal (1a) with allyltrimethylsilane in dichloromethane at room temperature in the presence of 4Å molecular sieves.Thus, a combination of 2 mol% InCl 3 and 20 mol% Me 3 SiCl was found to be the optimum condition for maximum yield and stereoselectivity (entry 6, Table 1).It may be mentioned that Cglycosylation in glucal, 1a can also be effected using ca 50 mol% Me 3 SiCl in excellent yield but with reduced stereoselectivity (entry 3, Table 1), whereas a stoichiometric amount of InCl 3 is necessary for the generation of allyl C-pseudoglycal (2a) from 1a in almost quantitative yield with very good stereoselectivity (entry 1, Table 1).Thus the enhancement of the catalytic activity and high stereoselectivity of the InCl 3 -Me 3 SiCl combination may involve a synergistic process.Accordingly, per-O-acetyl-D-glucal (1a) reacted with allyltrimethylsilane in the presence of 2 mol% InCl 3 and 20 mol% Me 3 SiCl at room temperature, in dichloromethane in the presence of molecular sieves within 1 hour affording the corresponding allyl C-glucoside in 90 % yield and 9:1 α-anomeric selectivity (entry 1, Table 2).
Similarly, per-O-acetyl-D-galactal (1b), -L-rhamnal (1c) and -D-arabinal (1d) also were converted efficiently to their respective C-pseudoglycals in excellent yields with nearly exclusive α-anomeric selectivities (entries 5-7, Table 2).The mild reaction condition was amicable towards benzyl and benzoyl protections also.Thus, the yields and α-anomeric selectivities of both allyl per-O-benzyl-and per-O-benzoyl-C-pseudoglucals (2e and 2f) were equally excellent under similar reaction conditions (entries 8 and 9, Table 2).Per-O-benzoyl-Dglucal (1f), however, needed the presence of 5 mol% InCl 3 and 20 mol% Me 3 SiCl for efficient conversion to the product.The efficacy of the combination catalyst system was further extended in the effective transformation of per-O-acetyl-D-lactal (1g) to its corresponding allyl C-pseudo lactal (2g) in nearly quantitative yield and exclusive α-selectivity (entry 10, Table 2).Other silyl nucleophiles, such as, trimethylsilyl cyanide and triethylsilane were also employed in such reactions in the presence of this catalyst system with the generation of the corresponding Cglycosyl cyanides (entries 11-13, Table 2) and unsaturated pyran derivatives (entries 14 and 15, Table 2) with equal efficacy.However, the anomeric selectivities of glycosyl cyanides were lower than those of the allyl C-pseudoglycals.The present catalyst system is equally effective in solvent free condition.Thus, 1a reacted in neat with allyltrimethylsilane in the presence of 2 mol% InCl 3 and 20 mol% Me 3 SiCl forming 2a within 5 minutes with equal efficacy (entry 2, Table 2).InCl 3 can be recovered and reused without any loss of its activity after the reaction (entry 3, Table 2).A similar efficiency of the catalyst system was observed in a scaled up experiment (6 fold) of 1a that also produced 2a in 92% yield and 9:1 α selectivity (entry 4, Table 2).
A plausible catalytic cycle of the reaction for regeneration of InCl 3 may be depicted as shown in Scheme 2. In this combination catalyst system, Me 3 SiCl probably assists in the regeneration of InCl 3 from the InCl 2 OR intermediates.In conclusion, we have demonstrated that InCl 3 in combination with Me 3 SiCl acts as an efficient catalyst system for stereoselective C-glycosylation of glycal derivatives.The advantages of the present method are: its operational simplicity, low catalyst load, excellent yields, excellent stereoselectivities with allyl C-pseudoglycals and the reusability of the recovered InCl 3 retaining its complete activity.The present methodology, thus constitutes an important addition and may gainfully substitute some of the existing procedures.

Experimental Section
General Procedures.All melting points are uncorrected.All known compounds were characterized by IR, NMR and by comparing their physical data with those in the literature.IR spectra were recorded on Perkin Elmer 297 spectrophotometer. 1 H-NMR spectra were recorded on Bruker DPX-300 (300 MHz) spectrometer using CDCl 3 as solvent and TMS as the internal standard.Optical rotations were measured on Perkin Elmer electronic polarimeter 241 or on Jasco digital polarimeter model P-1020.

Table 2 .
2 mol% InCl 3 and 20 mol% Me 3 SiCl catalysed Ferrier rearrangement of glycal derivatives with silyl nucleophiles a neat.b with recovered InCl 3.c scale up with 0.6g 1a.d reaction mixture was stirred at 20-25°.e in the presence of 5 mol% InCl 3 -20 mol% Me 3 SiCl.f isolated chromatographed yields.g anomeric ratios were determined by 1 H-NMR.h based on the isolated yields of anomers.